Magnetic material attracting/releasing control method making use of a pipette device and various types of analyzer using the method

ABSTRACT

A magnetic material attracting/releasing control method makes use of a pipette device sucking a liquid from or discharging a liquid into a container. A magnet body or bodies are provided in a liquid suction line of the pipette device, and any magnetic material contained in liquid sucked into the liquid suction line by magnetic force are deposited on the internal surface of the line. The magnetic material is released and discharged together with liquid from the liquid suction line to a state where the effect of the magnetic force generated by the magnet body is cut off.

FIELD OF THE INVENTION

The present invention relates to a novel magnetic materialattracting/releasing control method which can capture or diffuse amagnetic material. The invention also relates to various types ofanalyzer using the method.

It should be noted that, as defined in this specification, the "magneticmaterial" indicates not only to ball-like materials, but also togranular and corpuscular materials, and the form is not limited to asphere; any form is allowable.

BACKGROUND OF THE INVENTION

In recent years, a variety of chemiluminescence methods (CL method) havebeen developed, which include, for instance, an enzyme immunoassay (EIA)that utilizes an antigen-antibody reaction, a chemiluminesenceimmunoassay (CLIA) in a narrow sense in which a chemical illuminescentcompound is used for labeling as a tracer for immunoassay, and achemilluminescent enzyme immunoassay (CLEIA) which detects enzymeactivity with high sensitivity by using a chemical luminescent compoundin a detection system.

As an inspection method using any of the techniques as described above,there have been known the magnetic particle method using magneticparticles each having a surface coated with an antigen or an antibody,the latex method using latex having a surface coated with an antigen oran antibody, the beads method using spheric beads each having a surfacecoated with an antigen or an antibody, or the so-called tube coatingmethod using cells each having an inner wall coated with an antigen oran antibody. When taking into account efficiency of capturing an antigenor an antibody as well as production cost and running cost, However,methods using magnetic bodies such as magnetic particles or beads arefar more advantageous.

In the conventional type of inspection methods using a magnetic materialas described above, however, it is required to clean the magneticmaterial or have the magnetic material reacted to a reagent by gatheringthe magnetic material floating or depositing in a reactor, such as aspecimen reaction container, or generating a floating state thereofseveral times in the reactor, however, it is extremely difficult tomaintain high precision of gathering or agitating the magnetic materialin the process, and this is one of the reasons why the inspection methodmaking use of magnetic material has not been automatized for variousapplications.

Description is made of a flow in an immuno chemical process making useof a magnetic material as described above with reference to FIG. 9. Inthis flow, at first when a required quantity of specimen is sampled in acontainer 1 with a first pipette device P₁ in step (a), a reactioninsoluble magnetic liquid 3 is poured into the container 1 by a secondpipette device P₂ in step (b). Agitation by a vibrating agitator isexecuted in step (c), incubation (under a constant temperature) isexecuted in step (d), and attraction of magnetic material by a magnet Mand discharge of the liquid are executed in step (e). A cleaning liquidis then poured by a third pipette device P₃ into the container in step(f).

Then in step (g), agitation is carried out by an shaking agitator, instep (h), the magnetic material 2 is attracted by the magnet M with thecleaning liquid discharged, in step labeling liquid 6 is poured inthrough a fourth pipette device P₄, in step (j) agitation is carried outby a shaking agitator, in step (k) incubation (reason under a constantreaction) is carried out, then in step (l) the magnetic material isattracted by the magnet M With the reaction liquid discharged, in step(m) the cleaning liquid is poured in through a fifth pipette device P₅.Then, in step (n), agitation is carried out by the shaking agitator.

Then, for instance, in CLEIA method, in step (o) the magnetic material 2is attracted by the magnet M with the cleaning liquid discharged, instep (p) the carried liquid is poured in, in step (q) agitation iscarried out by a shaking agitator, and then in step (r) the sample isleft for a certain period of time, and in step (s) the quantity of lightemitted from the reaction system is measured with an optical measuringinstrument such as PMT.

On the other hand, in case of CLIEA method, after step (n) describedabove, in step (t) a cleaning liquid containing the magnetic material 2in the vessel 1 is sucked out with the cleaning liquid poured into ameasuring cell with a filter provided thereon, and the magnetic material2 contained in the cleaning liquid is collected by the filter. Then, instep (u), hydrogen peroxide liquid (H₂ O₂) is poured into the magneticmaterial 2 collected by said filter to have liquid emittedtransitionally, and a quantity of emitted light is measured by PMTtightly protected against light coming from outside.

On the other hand, in a checking method, like the CLEIA method or EIAmethod, in which light emission is continued for a certain period oftime after a substrate liquid is poured in step (s), in step (t) aquantity of light generated in the reaction is measured with an opticalmeasurement instrument such as a PMT.

The above description relates to the conventional type of inspectionmethod using a magnetic material, but as clearly understood from theforegoing, in the conventional inspection method making use of the typeof magnetic material as described above, it is required to attract themagnetic material onto the internal wall of a container and thenhomogeneously diffuse the attracted magnetic material into a liquidseveral times. It is extremely difficult to execute separation of themagnetic material from a liquid, agitation, and cleaning the containerat high precision, a problem to be solved.

Namely, when separating the magnetic material from a liquid, in theconventional type of inspection method, generally magnetic attraction isproduced on a side wall of a large container, requiring a long time toattract any magnetic material diffused in a liquid onto the internalwall of the container. Efficiency in gathering the magnetic materialthus is disadvantageously very low.

Also, when gathering magnetic material on the internal surface of acontainer and inserting a pipette into a liquid to absorb the liquid,the magnetic material may be absorbed together with the liquid, and itis extremely difficult to completely capture the magnetic material.

Furthermore, when agitating the liquid with magnetic material diffusedtherein, generally to eliminate magnetism in a magnet and mix anddiffuse the magnetic material once absorbed in liquid in the container,vibration is usually employed. However, it is difficult to diffuse themagnetic material in the liquid homogeneously, and the liquid containingthe magnetic material mixed therein sometimes splashes out onto an uppersurface of the container, another problem to be solved. As a result,with vibration as employed agitation in the conventional technology, awashing off the liquid containing magnetic material splashed out ontothe upper surface of the container is required. Hence, processingbecomes more complicated, and if this operation for washing off theliquid is carried out incompletely, the subsequent steps in the processare seriously affected.

Furthermore, when cleaning the liquid and magnetic material in thecontainer as described above, materials other than those deposited onthe surface of the magnetic material are removed by carring outprocesses for separating as well as agitating as described above, butthe same problems as those that arise in separating and agitating mayoccur.

Also, in the inspection method making use of the conventional type ofmagnetic material, if a reaction process or a treatment process is avery specific one, it is required to build mechanisms for separation,agitation, and cleaning as well as a control system suited to thespecific process. Hence, the mechanisms or the control system becomevery complicated, and it is practically impossible to carry out aninspection making use of a magnetic material based on a very specificreaction or treatment process. As a result, the facility or theoperating cost becomes very high.

In addition, in the method of gathering magnetic material based on theaforementioned conventional technology, it is difficult to position themagnet as described above in such a container as, for instance, amicroplate, and even if possible, it is difficult to position a magneton a side face of the container. It is also difficult to carry outseparation by attracting the magnetic material from a liquid, agitationand cleaning, and as a result it is extremely difficult to downsize thecontainer by using a microplate, a fatal disadvantage.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a magnetic materialattracting/releasing control method using a novel pipette, the mostremarkable feature of which consists in that capturing and gatheringmagnetic material diffused in a liquid from the liquid is not executedon the side of a container in which a specimen is accommodated but in apipette which can absorb and discharge the liquid containing themagnetic material. The pipette can realize substantial improvement ofmeasurement precision in an inspection method making use of this type ofmagnetic material by for complete attraction in a short period withmagnetism of a magnet provided on the absorption/discharge side of apipette chip or the like in this pipette device. Cross-contamination isprevented if a disposable pipette chip is used, and the method caneasily respond to various types of inspection each based on a specificreaction or treatment process, respectively. An inspection device usinga magnetic material can be produced material with the invention, simplein terms of construction and operation thereof and also more versatileand low in cost.

To achieve the objects as described above, in a magnetic materialattracting/releasing control method making use of a pipette according tothe present invention, a magnet is provided in a liquid suction line ina pipette for sucking and discharging a liquid from inside a container.Any magnetic material in a liquid attracted by the liquid suction linedue to magnetism in the magnet is absorbed and maintained on theinternal surface of the liquid suction line, and then the magneticmaterial is separated from the liquid suction line and dischargedtogether with the liquid from the liquid suction line.

In the present invention, to enhance processing capability, a pluralityof liquid suction lines are provided in parallel to each other. Suckingor discharging a liquid in each liquid suction line is driven andcontrolled so that absorption or separation of magnetic material in theliquid will be executed concurrently. This enables realization of amulti-channel system allowing concurrent processing of a plurality ofspecimens.

Furthermore, in the present invention, to enhance the processingcapability and respond to any liquid requiring a specific treatmentprocess, it is possible to provide a plurality of liquid suction linesdescribed above. Each liquid suction line is controlled independently ata different timing so that suction and discharge of liquid arecontrolled to attract or separate the magnetic material mixed anddiffused therein through a specific treatment process, respectively.

In the present invention, only at least one liquid suction line asdescribed above is required. Improvement in processing capability can beachieved only by integrating a liquid suction line and magnetic materialinto a unit and providing a plurality of units as described above alonga container transfer line.

Also, in the present invention, the magnet described above includes anytype of permanent magnet or electric magnet as far as it can generatemagnetism for attracting a magnetic material, and one or more pieces ofmagnet can be provided in each liquid suction line in correspondence tothe diameter of the liquid suction line, quantity of magnetic materialto be attracted, and size thereof. Various types of mode for locatingthe magnets can be considered, for instance, magnets may be located inthe direction in which a liquid flows in the liquid suction line or atopposite positions in both sides of the liquid suction line, or in theradial direction.

Furthermore, in the present invention, the above magnets can be locatedin the outside of the liquid suction line, or directly onto the liquidsuction line.

When locating magnets outside the liquid suction line as describedabove, by using a plurality pieces of permanent magnet as the magnetbodies above and locating the magnet bodies on or near the liquidsuction line, it is possible to absorb and maintain magnetic materialcontained in liquid attracted to the liquid suction line onto theinternal surface of the liquid suction line. It is further possible todischarge the magnetic material together with the liquid from the liquidsuction line by moving the magnetic bodies away from the liquid suctionline to separate the magnetic material from the line.

When directly locating the magnet bodies on or near the liquid suctionline, by forming the magnet bodies with electro-magnets and generatingmagnetism in the electro-magnets, it is possible to absorb and maintainmagnetic material contained in liquid sucked into the liquid suctionline on an internal surface of the liquid suction line. It is alsopossible to separate the magnetic material from the liquid suction lineby providing controls over the electro-magnets so that the magnetismdisappears or is reduced for discharging the magnetic material togetherwith the liquid from the liquid suction line. It is needless to saythat, for forming the electro-magnet as described above, an excitingcoil may directly be attached to the liquid suction line itself or thecoil may be wound around the liquid suction line. A configuration isalso allowable in which the electro-magnet can be moved closer to oraway from the liquid suction line.

As an important feature of the present invention, a liquid suction lineis formed by dismountably mounting a pipette chip onto a tip section ofthe liquid sucking side thereof. The magnet body is arranged so thatmagnetism generated by the magnet body works over magnetic materialinside the pipette chip.

Thus by making it possible, when sucking or discharging a liquidcontaining magnetic material with a pipette chip, to absorb the magneticmaterial obtained in the liquid onto an internal surface of the pipettechip, the magnetic material can be captured as completely as possible.It is also possible to transfer a pipette chip with magnetic materialdeposited on an internal surface thereof, as is, to a next reaction ortreatment step. This can not be realized without using the pipettedevice according to the present invention, and at least in that sensethe present invention is novel.

The pipette chip described above is used repeatedly only for the samespecimen in a process in which the specimen is processed according to aspecified processing sequence for inspection to preventcross-contamination. Any number of pipette chips may be used for thesame specimen according to the requirement for a reaction or a treatmentprocess in various types of inspection.

Also, in the present invention, if the liquid suction line is formedwith a nozzle system in which a pipette chip can not be loaded orunloaded, it is possible to separate the magnetic material from theliquid, agitate and clean the internal as well as external surface ofthe liquid-contacting section contacting liquid in the liquid suctionline by means of sucking or discharging the liquid to a degree wherecross-contamination will not occur.

Another feature of the present invention consists in that separation ofthe magnetic material from the liquid, agitation and cleaning can becarried out by sucking liquid into or discharging a liquid from theliquid suction line once or more than once.

Namely, in the present invention, separation of magnetic material from aliquid is executed by maintaining the state where magnetic material isabsorbed and deposited on the internal surface of a liquid suction lineand discharging only the liquid. This is alternatively accomplished byinserting a pipette chip with magnetic material attracted by a magnetbody and deposited on an internal surface thereof into liquid stored inan other container and repetitiously sucking and discharging the liquidto a state where the magnetic material is not affected by magnetism inthe magnet body described above.

Thus, by executing separation between a liquid and magnetic materialcontained in the liquid by means of repetitiously for sucking anddischarging the liquid in a liquid suction line of a pipette device, itis possible to almost completely capture the magnetic material. Thealmost complete separation of magnetic material from a liquid containingthe magnetic material can be realized in all processes requiringseparation of magnetic material from a liquid containing it.

Also, in the present invention, when a pipette chip is mounted on aliquid suction line, the agitation and cleaning steps described aboveare executed by transferring the pipette chip with magnetic materialattracted by the magnet body and deposited onto an internal surfacethereof as is to the position for agitation and cleaning and thenrepeating the operations for sucking and discharging the liquid. In thiscase, agitation and cleaning can be executed with the magnetic materialdeposited on an internal surface of a pipette chip or executing anoperation for sucking and discharging the liquid once or more to a statewhere the magnetic material is not affected by a magnet body.

As described above, with the present invention, it is possible tohomogeneously diffuse magnetic material in a liquid by sucking anddischarging the liquid in a liquid suction line in a pipette device. Itis also possible to improve the cleaning efficiency, and in addition,although liquid sucking and discharging is executed between a liquidsuction line and a container, the liquid containing magnetic materialdoes not splash out from the container. Hence, the agitation andcleaning processes can be executed under stable conditions withoutcausing the possibility of lowering precision in measurement due tosplashing of the liquid containing magnetic material.

It should be noted that, in the present invention, the operations forseparating magnetic material from a liquid containing it therein,agitation and cleaning can be executed by transferring a magnet body toa liquid containing magnetic material previously stored in a liquidstorage section in a cartridge having a plurality of liquid storagesections therein. Sucking or discharging the liquid is performedaccording to need, or by maintaining the state where magnetic materialis deposited on an internal surface of a pipette chip and dischargingthe residual liquid from the container. Then, liquid required for thenext process is poured into the same container and sucking ordischarging the liquid poured anew is carried out with the pipette chip.In brief, in the present invention, any specific form of a container isnot required for sucking and discharging liquid in a liquid suction lineto execute the operations for separating magnetic material from a liquidcontaining it therein, agitation, and cleaning.

Another significant feature of the present invention is that it ispossible to execute both qualitative and quantitative assessment of atarget material contained in a liquid by accurately controlling thequantity of liquid sucked by a liquid suction line.

The method according to the present invention is applicable to andeffective in a reaction generated between magnetic material and a liquidnot containing any magnetic material, a material present in a liquid,and other materials which can physically and chemically be deposited ona magnet body. The materials include immunological materials, biologicalmaterials, and molecular-biological materials such as antigens,antibodies, proteins, enzymes, DNA, vector DNAs, RNAs or plasmid. Themethod can be applied to inspection or a analyzer for isotopes requiredfor qualitative or quantitative analysis, enzymes, and other labelingmaterials used for chemiluminescence, fluoro-illuminescence, andelectro-chemical illuminescence or the like. For instance, the methodaccording to the present invention can be applied to apparatus forimmunological assay, inspections making use of chemical reaction,extraction, recovery and separation of DNAs.

For instance, if the method according to the present invention isapplied to an immunochemical inspection apparatus, a container is formedin a cassette having a plurality of liquid storage sections. A liquid orreagent required for reaction or processing is poured into each liquidstorage section, and the container should preferably be transferred witha magnetic material attracted by the magnet body to and deposited on aninternal surface of a liquid suction line as is. In this case, theliquid is previously poured into each liquid storage section asdescribed above, and only a portion thereof may be processed or beprocessed gradually in the treatment process.

Furthermore, a specimen can directly be measured quantitatively, forinstance, in a parent specimen container and then poured into eachliquid storage section. It should be noted that the liquid storagesections in the cassette may be arranged either in a single array or ina plurality of arrays and formed into a form like a microplate. If thecassette is a form like a microplate, a multi-channel system can berealized by locating a plurality of liquid suction lines incorrespondence to the liquid storage section arrays, and thus theprocessing capability is substantially improved.

Other objects and features of this invention will become understood fromthe following description with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart showing processes in a case where the presentinvention is applied to an immunochemical inspection method based on thechemiluminescence method;

FIG. 2 is a cross-sectional view showing an example of a pipette chipused in the present invention;

FIG. 3 is an explanatory view showing an example of the generalconfiguration of a measurement section in a case where the presentinvention is applied to an immunochemical inspection method based on theCLEIA method;

FIG. 4 is an explanatory view showing an example of the generalconfiguration of a measurement section in a case where the presentinvention is applied to an immunochemical inspection method based on theCLIA method;

FIG. 5 is an explanatory view showing an example of generalconfiguration of a measurement section in a case where the presentinvention is applied to an immunochemical inspection method based on theEIA method;

FIG. 6 is an explanatory view showing an example of the arrangement of amagnet in a case where a liquid suction line in the present invention isa nozzle system;

FIG. 7 is an explanatory view showing another example of an arrangementof a magnet in the present invention;

FIG. 8 is an explanatory view showing still another example of anarrangement of a magnet in the present invention; and

FIG. 9 is a flow chart showing processes in an immunochemical inspectionmethod based on the conventional type of chemiluminescence method.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Detailed description is made for a case where the present invention isapplied to an immunochemical inspection method based on thechemilluminescence method with reference to an embodiment of the presentinvention shown in the attached drawings. As described above, the fieldof application of the present invention is not limited to theembodiment, and the present invention can be applied to any case as faras a magnetic material attracting/releasing method making use of apipette device is applied and magnetic material is used.

A flow of an immunochemical inspection according to the presentinvention as compared to a flow of the conventional type ofimmunochemical inspection is described below with reference to FIG. 1.

It should be noted that, in this embodiment, the magnetic material isdefined as magnetic material, which can be adhered to a surface of anantigen or an antigen, being attracted by a magnet body for B/Fseparation (separation of materials bound to antigen or antibody andthose not bound to them).

In this figure, the sign P indicates a pipette chip for pouring aspecified quantity of specimen from a parent vessel, such as a bloodtube (not shown), into a specimen reaction container 1 and also fordischarging from or sucking into the specimen reaction container 1 areaction insoluble magnetic material liquid 3, a cleaning liquid 5, anenzyme-labeling liquid 6, a substrate liquid 7, a reaction stop liquid 8or the like.

As shown in FIG. 2, the pipette chip P has a three-staged formconsisting of a thinnest section 10 inserted into the specimen reactioncontainer 1, a medium diameter section 11 having a larger diameter thanthe thinnest section 10, and a large diameter section 12 having a largerdiameter than the medium diameter section 11. A magnet M for attractingthe reaction insoluble magnetic material 3 is detachably fitted to anexternal peripheral surface of the medium diameter section 11 with amechanism for sucking or discharging liquid in a cylinder or the likedisconnectably connected and communicated to a top edge section of thispipette chip P. It is needless to say that the form of this pipette chipP is not limited to that shown in this figure; any form is allowable onthe condition that, when a liquid is sucked into the pipette chip P, anymagnetic material contained in the liquid is captured by the magnet Mwithout fail. To completely capture the magnetic material with themagnet, however, it is desirable to form the section contacted by themagnet with a small diameter. This also is preferable for efficientlycontrolling flow rate while sucking or discharging liquid.

It should be noted that, when extracting, recovering, or separatingDNAs, a molded pipette chip having a large diameter may be used toprevent the DNAs from being broken or damaged due to physical forceeffecting magnetic material deposited on the DNAs and generated whenliquid is sucked or discharged.

In the specimen reaction container 1, a plurality of liquid storagesections 1A through 1H are provided in a straight array, in a loop, orin a zig-zag form with a roughly specified quantity of specimen havingbeen poured in the liquid storage section 1A, a specified quantity ofreaction insoluble magnetic material liquid 3 in the liquid storagesection 1B, a specified quantity of cleaning liquid 5 in the liquidstorage sections 1C and 1D, a specified quantity of labeling liquid inthe liquid storage section 1E, a specified quantity of cleaning liquid 5in the liquid storage sections 1F and 1G, each filled with the liquidbefore start of inspection, and a substrate liquid in the liquid storagesection 1H for measurement of the light-emitting state.

In the case of the CLIA or CLEIA inspection, the specimen reactioncontainer 1 is made of opaque material to prevent any effect byilluminescence, and in the case of the EIA inspection at least thebottom section is made of a transparent material.

When carrying out immunochemical inspection according to the presentinvention using the specimen reaction container 1 constructed asdescribed above and the pipette chip P, the specimen having been pouredinto the liquid storage section 1A by a roughly specified quantity issucked with the pipette chip P above by a specified quantity forquantitative analysis.

Then, the pipette chip P with the specimen sucked thereinto istransferred and all of the specimen having been sucked is dischargedinto the reaction insoluble magnetic material liquid 3 in the liquidstorage section 1B. A mixture of the specimen and the reaction insolublemagnetic material liquid 3 then is repeatedly sucked and discharged withthe pipette chip P (this operation is called liquid sucking/dischargehereinafter) to generate a state where the magnetic material 2 has beenhomogeneously agitated and mixed therein. In several hours, all, or aspecified quantity of, the incubated mixed liquid is sucked with thepipette chip P.

In this step, the magnetic material 2 floating in the mixed liquidsucked by the pipette chip P is captured onto an internal wall surfaceof the medium diameter section 11 due to magnetism of the magnet Mprovided outside the pipette chip P, as shown in FIG. 2, when the mixedliquid passes through the medium diameter section 11 of the pipette chipP. The mixed liquid is sucked into the pipette chip P to the heightshown in FIG. 2, so that, when all the mixed liquid is sucked into thepipette chip, the bottom face x comes near a lower edge of the magnet Mor to a level higher than that and the magnetic material 2 is completelycaptured.

After all the magnetic material 2 has been captured, the mixed liquidwith the magnetic material having been removed therefrom is dischargedinto the liquid storage section 1B, and only the magnetic material 2remains in the pipette chip P. As the magnetic material 2 is wet then,even if the mixed liquid is exhausted, the magnetic material 2 is keptdeposited on an internal surface of the medium diameter section 11 ofthe pipette chip P, so that, even if the pipette chip is transferred,the magnetic material rarely drops off from the internal surface. Thenthe pipette chip P is transferred to the next liquid storage section 1Cwith the magnetic material 2 captured therein, and sucks the cleaningliquid 5 in the liquid storage section 1C. Then the magnet M moves awayfrom the pipette chip P to release the magnetic material 2, andtherefore by sucking and discharging the cleaning liquid 5, all themagnetic material 2 can efficiently be cleaned.

After the operations for sucking and discharging the liquid arefinished, the pipette chip P slowly sucks all the cleaning liquid 5 (for5 to 10 seconds) in the liquid storage section 1C. Then the magnet M isagain moved toward the pipette chip P to capture all the magneticmaterial 2 floating in the sucked cleaning liquid 5, and the cleaningliquid 5 with the magnetic material 2 having been removed therefrom isdischarged into the liquid storage section 1C, so that only the magneticmaterial 2 remains in the pipette chip P.

Then the pipette chip P is transferred to the next liquid storagesection 1D with the magnetic material 2 captured therein and sucks thecleaning liquid 5 in the liquid storage section 1D, where the operationsfor cleaning and capturing the magnetic material 2 are executedaccording to the same sequence as that in the liquid storage section 1C.

Then the pipette chip P is transferred to the next storage section 1Ewith the cleaned magnetic material 2 captured therein, and sucks thelabeling liquid 6 in the liquid storage section 1E. Then the magnet Mmoves away from the pipette chip P to release the magnetic material 2,and thus by sucking and discharging the labeling liquid 6, all themagnetic material 2 and the labeling liquid 6 can be reacted to eachother homogeneously.

After the operations for sucking and discharging the liquid arefinished, incubation is continued for a specified period of time, andthen the pipette chip P slowly sucks all the labeling liquid 6 in theliquid storage section 1E (for instance, for 5 to 10 seconds). Then themagnet M again goes near the pipette chip P to capture all the magneticmaterial 2 floating in the sucked labeling liquid 6, and the labelingliquid 6 with the magnetic material 2 having been removed therefrom isdischarged into the liquid storage section 1E, and only the magneticmaterial 2 remains in the pipette chip P.

Then the pipette chip P is transferred to the next liquid storagesection 1F with the magnetic material 2 captured therein, sucks thecleaning liquid 5 in the liquid storage section 1F, executes operationsfor cleaning and capturing the magnetic material 2 according to the samesequence as those in the liquid storage sections 1C and 1D, sucks thecleaning liquid 5 in the liquid storage section 1G according to the samesequence as that for sucking the cleaning liquid in the liquid storagesection 1F, and then executes operations for cleaning and capturing themagnetic material 2.

Then the pipette chip P is transferred to the liquid storage section 1H,and for instance if a measurement in which illuminescence is continuedafter mixed with a substrate liquid and a certain period of time isrequired until a rate of light emission is stabilized as in the CLEIAinspection is to be carried out, the substrate liquid 7 previouslystored in the liquid storage section 1H is sucked by the pipette chip P.Then the magnet M moves away from the pipette chip P and releases themagnetic material 2, so that it is possible to homogenize the reactionbetween the magnetic material 2 and the substrate liquid 7 by suckingand discharging the substrate liquid 7.

When the operations for sucking and discharging the liquid have beenfinished and incubation has been executed for a certain period of time,a quantity of emitted light is measured by the optical measurementinstrument 9 such as a PMT as shown in FIG. 3.

In the case of an inspection method in which illuminescence is continuedonly for a very short period of time as in CLIA inspection, the liquidstorage section 1H is provided as shown in FIG. 4, a filter 16 and awater-absorbing pad 20 is provided in the liquid storage section 1H, andthe magnetic material 2 is discharged together with the cleaning liquid5 sucked in the previous process from the pipette chip P into the liquidstorage section 1H to have the magnetic material 2 captured by thefilter 16. Then a light-emitting trigger liquid 7 such as hydrogenperoxide liquid (H₂ O₂) is supplied from a nozzle 17 to make themagnetic material emit light, and a quantity of light emitted when saidsubstrate liquid is poured may be measured with an optical measurementinstrument 9 such as a PMT.

Furthermore, in the case of EIA inspection, after the substrate liquid 7is poured, a reaction stop liquid is supplied and as shown in FIG. 5, alight beam having a specified wavelength is irradiated from a bottomsection of the liquid storage section 1H, and a degree of absorbency ismeasured by a light-receiving element and a detector by checking thespecific color.

Thus, with the specimen reaction container 1 according to the presentembodiment, it is possible to respond to a plurality types ofimmunochemical inspection by changing only configuration of the liquidstorage section 1H in correspondence to various inspection methods, sothat the versatility can substantially be improved. Also a multi-channelsystem of this type can be realized by providing liquid storage sectionin a plurality of arrays in the specimen reaction container 1 to form itinto a form like a microplate.

Then the pipette chip P and the specimen reaction container 1 aredisposed.

It should be noted that, although description of the embodiment aboveassumed a case in which the specimen reaction container 1 is cleanedtwice after the reaction insoluble magnetic material liquid 3 isdischarged and furthermore 2 times after the labeling liquid 6 isdischarged, the present invention is not limited to the configurationdescribed above: the specimen reaction container 1 may be cleaned anynumber of times according to need.

Also the above description assumes the configuration in which thepipette chip P is transferred to each liquid storage section in thespecimen reaction container 1, but a configuration is allowable in whichthe pipette chip P is moved only in the vertical direction and thespecimen reaction container 1 is intermittently transferred forexecuting each of the operations described above.

Furthermore, the description of the above embodiment assumed a casewhere the pipette chip P and the specimen reaction container 1 aredisposable, although a configuration is allowable where the pipette chipP and the specimen reaction container 1 can be cleaned and usedrepeatedly. Also, the description of the above embodiment assumed a casein which the waste liquid after being sucked by the pipette chip P isrecycled to the original liquid storage section from which the liquidwas sucked. A configuration is also allowable, however, where the wasteliquid is returned to a waste liquid section provided outside thespecimen reaction container 1.

It is needless to say that the present invention is applicable to a casewhere the pipette chip P is not used and a liquid suction line is formedas a nozzle system, and in this case, the configuration as shown in FIG.6 is allowable where a lower edge section P_(A) of the liquid suctionline P₁ is formed into a thin diameter section, and the magnet M or anelectro-magnet is moved to or away from the lower edge section P_(A) ofthe liquid suction line P₁. When using the electro-magnet, aconfiguration is allowable where the electro-magnet is fitted to thethin diameter section of a liquid suction line or the electro-magnet isdirectly wound around the thin diameter section of the liquid suctionline and operations for separating magnetic material from a liquid,agitation, and cleaning are executed by turning ON or OFF a current.

Also, the description of the embodiment above assumes a case where themagnet M is detachably fitted to one side of the medium diameter section11 of the pipette chip P, but the magnets M may be provided in bothsides of the medium diameter section 11 as shown in FIG. 7. Also, aplurality of magnets M may be provided in a radial form around themedium diameter section 11 shown in FIG. 8, and also a plurality ofmagnets may be provided along the longitudinal direction of the mediumdiameter section 11, although that case is not shown herein.

As described above, in the present invention, magnetic material isloaded or unloaded by making use of a pipette device, and capture of themagnetic material is executed not in the side of a container in which aliquid is stored, but in the side of a liquid suction line for suckingand discharging a liquid containing magnetic material by making use ofmagnetism in a magnet provided therein, so that the magnetic materialcan almost completely be captured within a short period of time.

Also, in the present invention, a multi-channel system in which aplurality of specimens can be processed concurrently and the processingcapability can be enhanced by providing a plurality of the liquidsuction line described above and controlling the operations for suckingand discharging a liquid so that each liquid suction line absorbs orreleases magnetic material at the same timing respectively.

Furthermore, in the present invention, processing can be enhanced andvarious types of liquid each requiring a specific process can beprocessed by providing a plurality of liquid suction lines describedabove and controlling each of the liquid suction lines so that magneticmaterial is absorbed or released by sucking or discharging each liquidcontaining the magnetic material independently at a different timingaccording to a specified process required for each liquid.

The processing capability can be furthermore enhanced by integrating aliquid suction line and a magnet body into a unit and providing aplurality of units along the container transfer line.

In the present invention, when a liquid containing magnetic material issucked or discharged, the magnet material is absorbed onto an internalsurface of the pipette chip, so that the magnetic material can almostcompletely be captured, and the pipette chip can be transferred to thenext reaction process or processing step with the magnetic materialdeposited on the internal surface thereof.

The pipette chip is repeatedly used only for the same specimen in aprocess in which a specimen is processed according to a specifiedinspection method, so that cross contamination can be prevented. If theliquid suction line is based on a nozzle system in which a pipette chipis not loaded or unloaded, it is possible to prevent cross contaminationby cleaning an internal surface of the liquid suction line by means ofsucking and discharging a liquid.

Furthermore, in the present invention, operations for separatingmagnetic material from a liquid containing the magnetic materialtherein, agitation and cleaning are executed by sucking and dischargingthe liquid with the cleaned liquid suction line described above once ormore, so that the magnetic material can almost completely be captured.In addition, in the present invention, the operations of agitating andcleaning magnetic material are executed, as described above, in the sideof a liquid suction line of a pipette device by sucking and discharginga liquid, so that the magnetic material can homogeneously be diffused ina liquid, and also the cleaning efficiency can be improved. In addition,although sucking and discharge of a liquid is executed between a liquidsuction line and a container, the liquid containing magnetic materialnever splashes out. As a result, the operations of agitation andcleaning can be stabilized and precision in measurement does not becomelow due to contamination by the magnetic material containing liquidsplashing out.

In the present invention, a quantity of liquid to be sucked can becontrolled by the liquid suction line accurately, so that bothqualitative and quantitative analysis of a target material contained ina liquid can be executed with high precision.

Furthermore, the method according to the present invention can beapplied to various types of apparatus, and in this case a mechanismrequired for controlling magnetic material can substantially besimplified, and precision in measurement substantially improved andstabilized.

Although the invention has been described with respect to a specificembodiment for a complete and clear disclosure, the appended claims arenot to be thus limited but are to be construed as embodying allmodifications and alternative constructions that may occur to oneskilled in the art which fairly fall within the basic teaching hereinset forth.

What is claimed is:
 1. A magnetic substance attracting/releasing controlmethod comprises the steps of: providing a pipette device having aliquid suction line including a liquid inlet end for sucking a liquidcontaining said magnetic substance from a container and discharging saidliquid through said liquid inlet end, and a magnet body or magnet bodiesbeing detachably fitted to an external peripheral surface of said liquidsuction line of said pipette device; said pipette device providingattracting/releasing control by absorbing and maintaining said magneticsubstance contained in said liquid and attracted to said liquid suctionline due to magnetism in said magnet body or bodies on an internalsurface of said liquid suction line, said magnetic substance beingmaintained on said internal surface of said pipette device and also byreleasing said magnetic substance from said liquid suction line by meansof interrupting effect by magnetism in said magnet body or bodies sothat said substance is discharged together with said liquid to outsideof said liquid suction line through said liquid inlet end.
 2. A magneticmaterial attracting/releasing control method which comprises using apipette device according to claim 1, wherein a plurality of said liquidsuction lines are provided in parallel to each other and operations ofsaid liquid suction lines for sucking and discharging said liquid aredriven and controlled so that said magnetic material is concurrentlysucked and discharged at the same time respectively.
 3. A magneticmaterial attracting/releasing control method which comprises using apipette device according to claim 1, wherein a plurality of said liquidsuction lines are provided parallel to to one another, and each of saidliquid suction lines is driven and controlled so that a liquid in eachliquid suction line is sucked and discharged independently at adifferent time and through a specific process to each liquid suctionline respectively to attract or release magnetic material.
 4. A magneticmaterial attracting/releasing control method which comprises using apipette device according to claim 1, wherein said liquid suction lineand magnetic body or bodies are integrated into a unit and a pluralityof said units are provided along a container transfer line.
 5. Amagnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 1, wherein at least one unitcontaining said magnet bodies is provided on said liquid suction line.6. A magnetic material attracting/releasing control method whichcomprises using a pipette device according to claim 1, wherein saidmagnet body or bodies are provided outside said liquid suction line. 7.A magnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 1, wherein said magnet body orbodies are mounted on said liquid suction line.
 8. A magnetic materialattracting/releasing control method which comprises using a pipettedevice according to claim 1, wherein said magnet body comprises apermanent magnet, said magnetic material contained in said liquid andattracted by said liquid suction line is absorbed to and deposited onsaid internal surface of said liquid suction line by getting said magnetbody closer to said liquid suction line, and said magnetic material isdischarged together with said liquid to outside said liquid suction lineby separating said magnetic material from said liquid suction line bymeans of getting said magnet body away from said liquid suction line. 9.A magnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 1, wherein said magnet bodycomprises an electromagnet, said magnetic material contained in a liquidand attracted by said liquid suction line is absorbed and maintained onsaid internal surface of said liquid suction line by generating amagnetic force with said electromagnet, and said magnetic material isseparated from said liquid suction line and discharged together with aliquid from said liquid suction line when a magnetic force generated bysaid electromagnet is eliminated or fully reduced.
 10. A magneticmaterial attracting/releasing control method which comprises using apipette device according to claim 1, wherein a pipette tip isdismountably mounted onto a tip section of said liquid sucking side ofsaid liquid suction line to form said liquid suction line, and amagnetic force generated by said magnet body provides an effect overmagnetic material in a liquid stored in said pipette tip.
 11. A magneticmaterial attracting/releasing control method which comprises using apipette device according to claim 10, wherein said pipette tip istransferred to a specific processing position according to theparticular inspection method used with magnetic material absorbed andmaintained on said internal surface thereof.
 12. A magnetic materialattracting/releasing control method which comprises using a pipettedevice according to claim 10, wherein said pipette tip is repeatedlyused only for a single specimen according to the specified inspectionmethod required by said specimen.
 13. A magnetic materialattracting/releasing control method which comprises using a pipettedevice according to claim 10, wherein operations for separating saidmagnetic material from said liquid containing it therein, agitation andcleaning are executed after inside and outside of a liquid-contactingsection of said liquid suction line by means of sucking and dischargingsaid liquid repeatedly to a degree at which cross contamination does notoccur.
 14. A magnetic material attracting/releasing control method whichcomprises using a pipette device according to claim 1, whereinseparation of said magnetic material from said liquid containing ittherein, agitation, and cleaning operations are executed by conductingsaid operations for sucking and discharging said liquid with said liquidsuction line once or more.
 15. A magnetic material attracting/releasingcontrol method which comprises using a pipette device according to claim14, wherein said separation of magnet material from said liquidcontaining it therein is executed by discharging only said liquid withsaid magnetic material kept attracted by said magnet body.
 16. Amagnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 14, wherein said agitation isexecuted, after a pipette tip has been inserted into a liquid stored inanother container with magnetic material attracted on an internalsurface of said pipette tip by said magnet body, by sucking anddischarging said liquid repeatedly in a state where said operations arenot affected by a magnet force generated by said magnet body.
 17. Amagnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 14, wherein said cleaningoperation is executed, after a pipette tip is transferred to a cleaningposition with said magnetic material attracted onto an internal surfaceof said pipette tip by said magnet body, by sucking and discharging acleaning liquid repeatedly.
 18. A magnetic material attracting/releasingcontrol method which comprises using a pipette device according to claim14, wherein said cleaning operation with said cleaning liquid isexecuted with magnetic material attracted onto an internal surface ofsaid pipette tip.
 19. A magnetic material attracting/releasing controlmethod which comprises using a pipette device according to claim 18,wherein said cleaning with said cleaning liquid is executed by suckingand discharging said cleaning liquid once or more in a stage where saidcleaning operations are not affected by a magnetic force generated bysaid magnet body.
 20. A magnetic material attracting/releasing controlmethod which comprises using a pipette device according to claim 14,wherein said separation of magnetic material from a liquid containing ittherein, agitation, and cleaning are executed by sucking and discharginga liquid previously stored in a liquid storage section provided in acartridge with one or more liquid storage sections provided therein. 21.A magnetic material attracting/releasing control method which comprisesusing a pipette device according to claim 14, wherein said separation ofmagnetic material from a liquid in which it is contained, agitation, andcleaning are executed by discharging a residual liquid from saidcontainer to outside of said container with magnetic material depositedon an internal surface of a pipette tip then pouring a liquid requiredfor a subsequent processing into the same container, and sucking anddischarging the poured liquid with said pipette tip.